The major goal of this study is to determine the potential of rhamnetin, a natural plant flavanol, in maintaining resistance against oxidative stres and prevention of prostate cancer through klotho (KL) and Fox 'O' signaling in TRAMP mice. Aging is a major risk factor for prostate cancer and it has been proposed that the mechanisms of aging and prostate cancer are intimately related with each other. With increasing age, there is an increase in oxidative stress at cellular and organismal level, which correlates with reduced serum levels of secreted KL protein and loss of FOXO3a from the nucleus. Hence, there is an urgent need for an effective agent, which can reduce oxidative stress at cellular level. Rhamnetin, is a promising agent, ranks high in ORAC (Oxygen Radical Absorbance Capacity) scale may be an important new paradigm for reducing oxidative stress and impart cancer chemopreventive effects. The proposed study will explore the potential of rhamnetin in reducing oxidative stress at cellular level and compensate the loss of KL and FOXO3a in cell culture studies. Furthermore, in vivo studies will determine whether rhamnetin has potential to regulate KL and Foxo3a levels in the non-transgenic as well as in TRAMP model with increasing age, maintaining resistance against oxidative stress which could lead to inhibition of prostate cancer and disease free survival. Our long term goal is to develop a novel and effective preventive strategy for prostate cancer and to understand the basic mechanism of oxidative stress generation with increasing age in the regulation of prostate cancer development. Public Health Significance: There is an immediate need for the effective and clinically relevant strategies for inhibition of prostate cancer growth, mainly in high-risk individuals, without any side effects. Hereby using a novel agent from the clove and other herbal preparation, rhamnetin will be tested to prevent prostate cancer and prolong disease free survival. Since prostate cancer is a disease of aging male population and second largest killer after lung cancer in the United States, prevention strategies are urgently needed. PUBLIC HEALTH RELEVANCE: The proposed study will investigate the potential role of a natural compound, rhamnetin, in a diet- based strategy to maintain resistance against oxidative stress in the prevention of prostate cancer in a relevant Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. Klotho and Fox 'O' transcription factors are critical molecular targets involved in oxidative stress and aging, where the effects of rhamnetin has not been elucidated. Results obtained from these studies will provide supportive data and evidence to further test rhamnetin as a means to protect against prostate cancer.